1,3-Dialkyl- and other xanthine derivatives inhibit many of the pharmacological and physiological effects of adenosine, eg. the cardiac depressive,.sup.1 hypotensive,.sup.1 anti-diuretic,.sup.2 and anti-lipolytic effects,.sup.3 by acting as competitive antagonists at A.sub.1 and A.sub.2 -adenosine receptor subtypes. The naturally-occurring caffeine and theophylline, 1, are the most widely used xanthine drugs. However, they are non-selective and relatively weak adenosine antagonists (K.sub.i -values of 10 .mu.M or greater). Synthetic analogs of theophylline, containing 1,3-dipropyl-, 8-aryl, and 8-cycloalkyl-substitutions, are more potent as adenosine antagonists..sup.4-6 The combination of 1-, 3-, and 8-position substitutions has resulted in analogs such as CPX,.sup.5,6 2, and XAC,.sup.7 3, which are more than four orders of magnitude more potent than theophylline in binding at A.sub.1 -adenosine receptors, and A.sub.1 -selective by factors of 300 and 60, respectively.
Xanthines having thio-substitutions at the 2- and/or 6-position have been reported to act as antagonists as A.sub.2 -receptors in human fibroblasts.sup.21 and as phosphodiesterase inhibitors with potency comparable to or greater than theophylline..sup.8,9a Remarkably, 6-thiocaffeine and 6-thiotheophylline cause cardiac depression rather than stimulation..sup.9b Recently, 6-thiocaffeine and 6-thiotheophylline were reported to induce tracheal relaxation, without cardiac or behavioral stimulation..sup.9a Thio-substitution of the NH at position 7 of 8-phenyltheophylline reduced activity by 1000-fold at an A.sub.1 receptor and by nearly 100-fold at an A.sub.2 receptor..sup.20